Recent observations in man have served to re-emphsize the important role of 25 OH vitamin D (25 OH D) in the regulation of bone metabolism and the therapy of rickets and osteomalacia. Very little is known regarding the control of 25 OH D production as affected by drugs or pregnancy. Although it is recognized that anticonvulsant-induced osteomalacia is attended by decreased blood levels of 25 OH D, the mechanisms by which this occurs is unknown since it has been evaluated only a) in subcellular fractions of the hepatocyte, or b) after acute (4-10 day) therapy with anticonvulsants. Ketogenic diet therapy, which results in systemic acidosis, is currently being employed as an adjunct to anticonvulsant drugs in the treatment of seizure disorders. The combined treatment regimen of anticonvulsant drugs and ketogenic diet therapy may be exerting additive deleterious effects on hepatic 25 OH D production. I have recently shown that alcohol ingestion by the pregnant rat is attended by decreased fetal accumulation of [unreadable]3[unreadable]H-25 OH D. Since ethanol-induced alterations in vitamin D metabolism during gestation may be contributing to the development of the fetal alcohol syndrome, the effect of alcohol on 25 OH D production by the maternal and fetal rachitic liver will be studied. I will use the perfused rachitic rat liver to investigate the effects of chronic phenobarbital and diphenylhydantoin therapy, metabolic acidosis, the combination of anticonvulsant drugs and acidosis, and alcohol on the regulation of hepatic 25 OH D synthesis. Livers will be perfused with [unreadable]3[unreadable]H-vitamin D (23 pmoles) and the production of [unreadable]3[unreadable]H-25 OH D determined by Sephadex chromatography. Since 25 OH D is produced by both hepatic microsomes and mitochondria, the perfused liver system allows the evaluation of total hepatic 25 OH D synthesis by the various subcellular fractions. The maximum rate of [unreadable]3[unreadable]H-25 OH D production, the biliary excretion of vitamin D metabolites, the role of intrahepatic metabolites in the control of 25 OH D synthesis and the apparent k[unreadable]m[unreadable] of the 25 hydroxylation will be evaluated as affected by the drugs, acidosis, and alcohol. The effect of 25 OH D, 1,25(OH)[unreadable]2[unreadable]D, chronic anticonvulsant therapy, acidosis, and alcohol on the 25-hydroxylase in the rat liver homogenates, hepatic microsomes and mitochondria will be determined and compared to that of the perfused liver.